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Nuclear Factor-B Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer

Departments of ¹ Cancer Therapy and Research, ² Anatomic Pathology, and ³ Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Requests for reprints: Mitsuo Katano, Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6941; Fax: 81-92-642-6221; E-mail: mkatano{at}tumor.med.kyushu-u.ac.jp.

The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-B (NF-B), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-B p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-B suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-B by inflammatory stimuli, including interleukin-1ß, tumor necrosis factor-, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-B. NF-B-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-B suppressed the enhanced cell proliferation. Our data suggest that NF-B activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-B activation in part through Shh overexpression. (Cancer Res 2006; 66(14): 7041-9)

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